Host physiology changes rapidly to a serious infection including alterations in circulation, metabolism and neuro-endocrine function. Central to the patho-physiology of burn sepsis is the sequential change in macrophage cytokine signals (hyper response to hypo response) in the periphery and in tissues. This phase of immune-paralysis renders the critically injured patients succumb to nosocomial infections. Decrease in hyper-responsive or an increase in hypo-responsive monocytes may in part be the reason behind injury induced immune suppression. It is still unclear what cellular mechanisms steer monocyte replenishment and how the phenotype of circulating monocyte subsets influence the pathophysiology of sepsis. Our laboratory has shown that burn sepsis is associated with elevated catecholamine levels in the bone marrow that leads to monocytopoiesis and cytokine release in macrophages derived from bone marrow progenitors portending bone marrow as the origin of injury induced changes. We have published that burn sepsis also significantly alters ?- adrenergic receptor profile in bone marrow monocyte progenitors and recently we have elucidated the presence of adrenergic receptors on bone marrow hematopoietic stem cells (HSC), the primary source of peripheral and tissue monocytes that reside in the highly innervated bone marrow. Based on our preliminary data we hypothesize, thermal injury and sepsis promote a catecholamine rich niche in the bone marrow early on and skews the commitment and development of hematopoietic paradigm through adrenergic receptor engagement of HSCs. The newly forming monocytes under the aegis of post-traumatic milieu will then egress/migrate into circulation and tissues whose hypo responsive phenotype will likely dictate the subsequent immune responses. In Aim 1 we will interrogate the impact of 2-adrenergic receptor stimulation of HSCs on myeloid lineage commitment and monocyte/macrophage differentiation after thermal injury and sepsis and the influence of the altered differentiation paradigm on the phenotype of peripheral blood monocytes. In Aim 2 we will elucidate the transcriptional regulation governing 2-adrenergic receptor induced HSC lineage commitment. Given the key role of HSCs in monocyte/MX development and the important role of MX in host immune responses as well as the wide use of adrenergic agonists and antagonists in critically injured patients, the results gleaned from our aims will form a biological basis for proper understanding of the impact of catecholamine treatment on immune cell development and function in critically injured burn and trauma patients. PUBLIC HEALTH RELEVANCE Impairments in immune cell functions predispose critically injured burn patients to sepsis often resulting in death. The primordial and early sympathetic response system in host-defense results in profound increase of catecholamines within the bone marrow. Since all immune cells are formed in the bone marrow from hematopoietic stem cells, we are studying the effect of catecholamine in the development and function of hematopoietic stem cells in critical burn injury.